Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment
Francesca Polverino, Tianshi David Wu, Joselyn Rojas, Xiaoyun Wang, Jonathan J. Mayo, Michael Tomchaney, J. Tram, Samuel E. Packard, Duo Zhang, Kristan H. Cleveland, Elizabeth Córdoba-Lanús, Caroline A. Owen, Ashraf Fawzy, Gregory L. Kinney, Craig P. Hersh, Nadia N. Hansel, Kevin Doubleday, Maor Sauler, Yohannes Tesfaigzi, Julie G. Ledford, Ciro Casanova, Jaroslaw W. Zmijewski, John P. Konhilas, Paul R. Langlais, Rick G. Schnellmann, Irfan Rahman, Meredith C. McCormack, Bartolomé R. Celli
Abstract
Abstract Rationale Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, and emphysema, as well as systemic pathologies. Metformin is beneficial for protecting against aging-related diseases. Objectives We sought to investigate whether metformin may ameliorate CS-induced pathologies of emphysematous chronic obstructive pulmonary disease (COPD). Methods Mice were exposed chronically to CS and fed metformin-enriched chow for the second half of exposure. Lung, kidney, and muscle pathologies, lung proteostasis, endoplasmic reticulum (ER) stress, mitochondrial function, and mediators of metformin effects in vivo and/or in vitrowere studied. We evaluated the association of metformin use with indices of emphysema progression over 5 years of follow-up among the COPDGene (Genetic Epidemiology of COPD) study participants. The association of metformin use with the percentage of emphysema and adjusted lung density was estimated by using a linear mixed model. Measurements and Main Results Metformin protected against CS-induced pulmonary inflammation and airspace enlargement; small airway remodeling, glomerular shrinkage, oxidative stress, apoptosis, telomere damage, aging, dysmetabolism in vivo and in vitro; and ER stress. The AMPK (AMP-activated protein kinase) pathway was central to metformin’s protective action. Within COPDGene, participants receiving metformin compared with those not receiving it had a slower progression of emphysema (−0.92%; 95% confidence interval [CI], −1.7% to −0.14%; P = 0.02) and a slower adjusted lung density decrease (2.2 g/L; 95% CI, 0.43 to 4.0 g/L; P = 0.01). Conclusions Metformin protected against CS-induced lung, renal, and muscle injury; mitochondrial dysfunction; and unfolded protein responses and ER stress in mice. In humans, metformin use was associated with lesser emphysema progression over time. Our results provide a rationale for clinical trials testing the efficacy of metformin in limiting emphysema progression and its systemic consequences.